Typical absence epilepsy (AE) is a distinctive form of idiopathic generalized epilepsy (IGE) that affects about 1/1000 Children by age 15. AE is characterized by brief episodes of unresponsiveness associated with diffuse, 3-Hz spike-wave paroxysms on the electroencephalogram (EEG). Twin and family studies show that AE is a complex genetic trait. A critical step in the genetic dissection of AE is the chromosomal mapping of susceptibility loci, which will ultimately require genome- wide, model-independent linkage analysis in a large collection of pairs of affected relatives. Basic information regarding familial recurrence risks of AE is essential for the sound design and execution of such a major project. The power to detect linkage in a sample of affected relative pairs is critically influenced by the "recurrence risk ratio," or lambda, defined as the risk of a disease in a particular type of relative (e.g., a sibling) of a proband compared to risk in the general population. More specifically, power to detect an individual susceptibility locus is determined by its contribution to the overall recurrence risk ratio. Previous studies of familial recurrence of AE are limited by ascertainment bias, small sample size, and lack of adjustment for age. The first objective of this project is to generate unbiased, age-adjusted estimates of lambda for siblings, parents, and aunts/uncles of probands with AE. We will accomplish this by collecting family history information from 300 AE probands by structured interview. The phenotype of affected relatives will be confirmed by review of medical records and EEGs. We will compare our estimates of AE recurrence risk ratios with those predicted by various multilocus models. This analysis will suggest the degree of epistasis (interaction) between AE loci and the maximal effect that may plausibly be attributed to a single locus. Our second objective is to characterize a large cohort of AE subjects for (1) association studies of candidate genes implicated in genetic and pharmacologic animal models and (2) additional clinical investigations, including the identification of risk factors for drug-resistance or failure to remit and the evaluation of treatment regimens for patients with unsatisfactory responses to first-line therapy. This will be accomplished by expanding our existing AE clinical database/DNA repository. The support provided by this award will allow the principal investigator to reduce his clinical and administrative responsibilities, expand his research effort, and provide mentoring to young investigators considering careers in patient-oriented research project. It is anticipated that these individuals will apply the principals they learn from this mentored research experience to other neurodevelopmental disorders with a complex genetic basis.